Adenosine receptors: novel targets for drug development in allergic rhinitis

Adenosine is an endogenous nucleoside consisting of the purine base, adenine, in glycosidic linkage with the sugar ribose. Adenosine is normally present at low concentrations in the extracellular space and its levels are greatly increased during inflammation and tissue injury as a result of enzymatic cleavage of the nucleotide adenosine 5′-monophosphate (AMP) by the 5′-nucleotidase. This excess in adenosine levels may function as a 'retaliatory metabolite' by eliciting a number of protective responses against injury and inflammation [1]. Elevated levels of adenosine have been found in bronchoalveolar lavage fluid and exhaled breath condensate of patients with allergic asthma [2, 3]. Increased formation of adenosine can also occur in chronically inflamed upper airways as recently observed in exhaled breath condensates from patients with allergic rhinitis [4]. Consistent with the hypothesis of adenosine playing an important role in the pathogenesis of chronic inflammatory disorders of the upper airways, we have previously shown that nasal provocation with AMP elicits dose-related rhinitic symptoms and an immediate rise in histamine and tryptase levels in the nasal lavage fluid of individuals with allergic rhinitis [5–7]. In addition, an important deterioration in nasal patency has been objectively documented as a fall in peak nasal inspiratory flow from baseline after nasal AMP challenge [8]. Taken together, these observations suggest that adenosine signaling could regulate important features of rhinitis. Therefore, selective agonist or antagonist for adenosine receptor subtypes may represent valuable targets for drug development in allergic rhinitis. Extracellular adenosine elicits its effects by interacting with four cell surface G protein-coupled receptors that have been cloned and pharmacologically characterized; these are designated as A1, A2A, A2B and A3 adenosine receptors [9]. Adenosine receptors can be distinguished according to their preferred mechanism of signal transduction: A1 and A3 receptors interact with pertussis toxin-sensitive G proteins of the Gi and Go family; the canonical signaling mechanism of the A2A and of the A2B receptors is stimulation of adenylate cyclase via Gs proteins. In addition to the coupling to adenylate cyclase, all four subtypes may positively couple to phospholipase C via different G protein subunits. A1 adenosine receptors have high affinity for adenosine and are widely distributed in mammals, particularly in the brain, heart, kidney, respiratory smooth muscles and nerve terminals. A1 receptors are likely to be involved in depression of neurotransmission, autonomic control of cardiac function, bronchoconstriction and inflammatory responses induced by adenosine in some species. Although elegant experimental work in allergic rabbits suggest that the A1 receptor may be involved in the early response to allergen-induced asthma [10, 11], the relevance of these observations to allergic rhinitis is highly unlikely. A2A receptors have been localised to areas of the central nervous system, vasculature and cells of the immune system. Their main function is vasodilatation and inhibition of platelet aggregation. It is possible that adenosine may act through A2A receptors as an endogenous modulator of immune responses, by inhibiting the release of mediators of inflammation from a range of human cell types including granulocytes, mononuclear cells and mast cells; these inhibitory activities of the A2A receptors predominates at low concentrations of adenosine [12, 13]. Consistent with the hypothesis that A2A receptor activation could result in suppression of allergic inflammation, the selective A2A receptor agonist CGS 21680 proved to have considerable anti-inflammatory activity in a murine model of allergic asthma [14]. The functional significance of these receptors in the context of allergic rhinitis is likely to be associated with their vascular-mediated effects. In allergic rhinitis, the nasal vasculature may respond to adenosine by increasing nasal blood flow and restricting venous sinusoidal drainage with resulting nasal congestion and blockage. Functional human adenosine A2B receptors have been identified in smooth muscle cells, lung fibroblasts, endothelial cells, bronchial epithelium, and mast cells. The activity of A2B receptors predominate at high concentrations of adenosine. There is now evidence that a specific functional antagonism at A2B receptors level is also producing anti-inflammatory effects. In ADA deficient mice, treatment of an A2B antagonist, CVT-6883, inhibited airway inflammation as determined by the number of inflammatory cells in broncholaveolar lavage fluid as well as the expression of pro-inflammatory cytokines and chemokines [15]. Of particular relevance to the pathogenetic mechanisms of allergic rhinitis are those A2B receptors found in the mast cells because selective A2B receptor antagonists are known to potently suppress adenosine-induced mediator release (es. histamine, tryptase, prostanoids, leukotrienes) from human mast cells [16]. The role of the A3 receptor in the pathogenesis of allergic airways diseases is complicated by major pharmacological dissimilarities between species [17]. In man, relatively high density of functionally active A3 receptors are expressed in human eosinophils of patients with asthma [18] and appear to be involved in the inhibition of eosinophil chemotaxis when stimulated [19]. Furthermore, inhibition of important pro-inflammatory functions of human eosinophils by the selective A3 receptor agonist, IBMECA has been reported [20]. Since inflammation in allergic rhinitis is characterized by eosinophilic infiltration of the airways, it is possible that the elevated adenosine concentrations associated with allergic inflammation would contribute to inhibition of mucosal inflammation of through stimulation of eosinophils-expressed A3 receptors. All four adenosine receptor subtypes are normally expressed in several inflammatory and structural cells involved in allergic airway inflammation, but ultimately the spectrum of biological responses of adenosine appears to be dictated by the different pattern of receptors distribution and/or affinity occurring under certain circumstances (es. inflammation, injury). In many tissues, A1 and A2A receptors are present in relatively high amounts and can be activated by the physiological levels of adenosine and thus mediate the stimulant action of adenosine. On the other hand, A2B and A3 receptors appear to have relatively lower affinities and/or receptor reserves for adenosine and require higher concentrations of adenosine for their activation. However, the tissue adenosine levels in many pathophysiological conditions are raised to sufficiently high levels to activate the A2B and A3 receptors. Given the important role of adenosine and its receptors in orchestrating different aspects of airway inflammation, it is not surprising that the pharmaceutical industry has invested substantial resources in order to exploit several selective agonists or antagonists to these receptors subtypes in an attempt to generate novel therapies for inflammatory disorders of the airways [21]. Although predominant cellular localization, pattern of expression, level of affinity and functions of these receptors in the human nose have never been investigated, pharmacological modulation of adenosine receptors may be considered a valuable therapeutic approach for allergic rhinitis. That pharmacological activation of adenosine receptors is an important mechanism in allergic rhinitis is suggested by earlier work with theophylline, a drug that is known to acts as a non selective adenosine receptor antagonist by blocking A1 A2A and A2B receptors at clinical concentrations. In a small double-blind crossover study, treatment out of season of rhinitic patients with theophylline reduced the release of mediators from mast cells and attenuated sneezing after nasal allergen challenge [22]. Another controlled study in patients with seasonal allergic rhinitis demonstrated that treatment with theophylline reduced symptoms, nasal obstruction, eosinophils influx and ECP concentration in nasal lavage fluid after nasal allergen challenge [23]. Similar studies with topical corticosteroids found an effect on nasal obstruction of the same order of magnitude. Although it is difficult to compare drug effects between various studies with different set-ups and different patients, one might conjecture that the efficacy of oral theophylline is comparable to that of nasal corticosteroids. Hence, even unselective adenosine receptors antagonists such as theophylline may provide an alternative strategy to corticosteroids for the treatment of patients with allergic rhinitis. Following a similar logic, the article by Rimmer and colleagues [24] in this issue of the Journal addresses the role of adenosine signalling in patients with allergic rhinitis by evaluating the efficacy of intranasal treatment with a potent adenosine A2A receptor agonist with competitive antagonistic effects on the adenosine A3 receptor. They found that this drug improved to some extent nasal blockage but had no significant effect on rhinorrea, number of sneezes or peak inspiratory flow measurements. This is consistent with the notion that A2A receptor antagonism may result in reduction in nasal blood flow with resulting improved nasal congestion and blockage. Moreover, the drug significantly reduced tryptase release, but the levels of other inflammatory mediators in the nasal lavage. As correctly pointed out by Rimmer and colleagues [24], this drug showed limited clinical benefit in allergic rhinitis, even if it reduced some mediators released after allergen challenge. Perhaps this is not surprising, given a number of methodological problems with the study protocol. For example, it is possible that greater doses of the drug may be required to assess the full potential of adenosine signalling blockade in allergic rhinitis. Testing the hypothesis that adenosine signalling may have a role in allergic rhinitis with a drug characterised by a complex pharmacological profile adds also to the overall difficulty in interpreting the study findings. As a matter of fact, the observed limited clinical efficacy reported by the authors could be related to the fact that adenosine A3 receptors are not (or less likely to be) involved in mast cell activation after allergen challenge in allergic rhinitis and that A2B receptors could be upregulated in response to the higher level of activation of A2A receptors. Although the present study added to the literature in this area, it failed to reach any definite conclusions about the role of adenosine signalling in allergic diseases such as allergic rhinitis. Selective A2B antagonists, more potent and selective than theophylline, are currently being developed for asthma; these drugs have shown to attenuate inflammation, are known to potently suppress adenosine-induced mast cell mediator release, and could therefore be more promising candidates for the treatment of allergic rhinitis. However, as the biological responses of adenosine are ultimately dictated by the different pattern of receptors distribution and/or affinity in specific cell types depending on the tissue milieu, a complete and full characterization of adenosine receptor subtype distribution in the nose and the specific role of each receptor in the response of the upper airways to adenosine is mandatory. Without this information, attempts at elucidating the role of adenosine receptors as valuable therapeutic targets in allergic rhinitis are likely to end up in a fiasco. Supported by an educational grant by the University of Catania. Prof. R. Polosa is a consultant with CVT and Duska Therapeutics that have interests in adenosine receptors antagonists.